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Extra-Hepatic Manifestations of Nonalcoholic Fatty Liver Disease: A Review

  • Raseen Tariq
    Affiliations
    Department of Medicine, University of Rochester, Rochester, NY, USA
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  • Page Axley
    Affiliations
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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  • Ashwani K. Singal
    Correspondence
    Address for correspondence: Ashwani K. Singal, MD Associate Professor of Medicine, Division of Gastroenterology and Hepatology, University of South Dakota Sanford School of Medicine, Transplant Hepatologist Avera University Hospital & Transplant Institute, Chief Clinical Research Affairs, Transplant Hepatology & Institute of Human Genetics Research, Sioux Falls, SD, 57105, USA.
    Affiliations
    Division of Gastroenterology and Hepatology, University of South Dakota Sanford School of Medicine, Transplant Hepatologist Avera University Hospital & Transplant Institute, Chief Clinical Research Affairs, Transplant Hepatology & Institute of Human Genetics Research, Sioux Falls, SD, 57105, USA
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Published:August 17, 2019DOI:https://doi.org/10.1016/j.jceh.2019.07.008
      Nonalcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease worldwide with a strong association with metabolic syndrome. NAFLD is truly a systemic disease and is associated with a plethora of extra-hepatic manifestations or comorbidities. These are either related to secondary effects of associated obesity or from pathophysiological effects of insulin resistance in NAFLD. Three most common causes of increased morbidity and mortality associated with NAFLD are cardiovascular disease, liver disease, and cancer. In this narrative review, we will discuss comprehensively on cardiovascular disease, type 2 diabetes mellitus, and chronic kidney disease and will also highlight on malignancy especially colorectal cancer, pulmonary disorders including obstructive sleep apnea, endocrine disorders such as hypothyroidism and polycystic ovarian syndrome, dermatological disorders especially psoriasis, and hematological associations including iron overload and susceptibility to thrombosis. In addition to focusing on pathogenesis of these extrahepatic manifestations, we will highlight their clinical implications for physicians in routine clinical practice. Further, there remains an unmet need for safe and effective therapies and examining their benefits on these extra-hepatic manifestations among patients with NAFLD.

      Keywords

      Abbreviation:

      CKD (chronic kidney disease), CT (computed tomography), CVD (cardiovascular disease), MetS (metabolic syndrome), NAFL (nonalcoholic fatty liver), NAFLD (nonalcoholic fatty liver disease), NASH (nonalcoholic steatohepatitis), OSA (obstructive sleep apnea), PCOS (polycystic ovarian syndrome), T2DM (type 2 diabetes mellitus)
      During the past few decades, the prevalence of nonalcoholic fatty liver disease (NAFLD) has significantly increased in parallel with increasing obesity, and it is now the leading cause of chronic liver disease in the United States and worldwide.
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      Nonalcoholic fatty liver disease: a challenge for pediatricians.
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      Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
      The prevalence of NAFLD is higher among patients with dyslipidemia and type 2 diabetes mellitus (T2DM) compared with the general population
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      Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.
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      Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease.
      ; additionally, there is evidence that NAFLD might have a role in the development of T2DM and metabolic syndrome (MetS) rather than just being one of its manifestations.
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      NAFLD: a multisystem disease.
      It should be recognized that most of the studies have defined NAFLD based on ultrasound and/or computed tomography (CT) scan which can miss mild steatosis, and these patients may have been included in the healthy population without NAFLD. The pathogenesis of occurrence of liver inflammation and fibrosis in patients with NAFLD is not completely understood. Other than insulin resistance, iron abnormalities have been thought to be one of the triggering factors. However, studies have not favored iron overload and hemochromatosis gene (HFE) gene mutations as major factors in the pathogenesis of nonalcoholic steatohepatitis (NASH) in Asian Indians.
      NAFLD encompasses a wide spectrum of disease including nonalcoholic fatty liver (NAFL) and NASH which is characterized by liver inflammation with potential to progress to advanced fibrosis, cirrhosis, and hepatocellular carcinoma. In 80% of patients, NAFLD is histologically characterized as NAFL and NASH is present in 20% of patients.
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      Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.
      The mortality among patients with NAFLD is higher compared with general population with most common causes of death being cardiovascular events, malignancy, and liver-related mortality.
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      Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease.
      Studies demonstrate that the degree of liver fibrosis among patients with NASH is independently associated with mortality, liver transplantation, and liver-related outcomes.
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      • Dam-Larsen S.
      • et al.
      Liver fibrosis, but No other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.
      There is growing evidence to support that NAFLD is a multisystem disease, and it involves extra-hepatic organ systems (Figure 1).
      • Adams L.A.
      • Anstee Q.M.
      • Tilg H.
      • Targher G.
      Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases.
      To date, most of the studies have evaluated the association of NAFLD with cardiovascular disease (CVD), T2DM, and chronic kidney disease (CKD). Studies have also suggested association of NAFLD with colorectal cancer, obstructive sleep apnea (OSA), polycystic ovarian syndrome (PCOS), and hypothyroidism. In this review, we briefly discuss the current literature regarding the pathogenesis and clinical implications of these associations among patients with NAFLD.
      Figure 1
      Figure 1Nonalcoholic fatty liver disease (NAFLD): a multisystem disease. Reported associations between NAFLD and various human diseases.

      NAFLD and Cardiovascular Disease

      There is a strong association between NAFLD and atherosclerosis, as NAFLD patients have numerous established risk factors for CVD including insulin resistance, dyslipidemia, and obesity.
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American association for the study of liver diseases, American College of Gastroenterology, and the American Gastroenterological association (vol 107, pg 811, 2012).
      Further, risk for CKD is increased in NAFLD, which in itself is a risk factor for development of CVD. In addition to these established risk factors, insulin resistance and MetS in NAFLD is associated with other nontraditional risk factors for atherosclerosis such as elevated serum uric acid level, proinflammatory markers including C-reactive protein, interleukin-6, leptin, tumor necrosis factor-alpha, circulating free fatty acids, and decreased levels of antiinflammatory hormone adiponectin.
      • Byrne C.D.
      • Targher G.
      NAFLD: a multisystem disease.
      • Targher G.
      Relationship between high-sensitivity C-reactive protein levels and liver histology in subjects with non-alcoholic fatty liver disease.
      • Sirota J.C.
      • McFann K.
      • Targher G.
      • Johnson R.J.
      • Chonchol M.
      • Jalal D.I.
      Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: liver ultrasound data from the National Health and Nutrition Examination Survey.
      In addition, other markers of atherosclerosis are increased in NAFLD patients independent of MetS with carotid atherosclerotic plaques and rupture,
      • Sookoian S.
      • Pirola C.J.
      Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review.
      endothelial dysfunction,
      • Villanova N.
      • Moscatiello S.
      • Ramilli S.
      • et al.
      Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease.
      increased carotid intimal thickness,
      • Volzke H.
      • Robinson D.M.
      • Kleine V.
      • et al.
      Hepatic steatosis is associated with an increased risk of carotid atherosclerosis.
      and increased coronary artery calcification.
      • Kim D.
      • Choi S.Y.
      • Park E.H.
      • et al.
      Nonalcoholic fatty liver disease is associated with coronary artery calcification.
      These pathological changes along with physiological abnormalities of impaired myocardial perfusion result in structural changes in the myocardium with increased remodeling and with increased myocardial fat content, impaired ventricular relaxation, aortic valvular sclerosis, and arterial stiffness.
      • Pacifico L.
      • Di Martino M.
      • De Merulis A.
      • et al.
      Left ventricular dysfunction in obese children and adolescents with nonalcoholic fatty liver disease.
      All these changes result in impaired myocardial energy metabolism as assessed on magnetic resonance spectroscopic examination, resulting in diastolic dysfunction and heart failure.
      • VanWagner L.B.
      • Wilcox J.E.
      • Colangelo L.A.
      • et al.
      Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: a population-based study.
      Additionally, NAFLD is independently associated with risk for ventricular arrhythmias including atrial fibrillation, prolongation of QT interval, cardiac autonomic dysfunction, and sudden cardiac death.
      • Targher G.
      • Valbusa F.
      • Bonapace S.
      • et al.
      Non-alcoholic fatty liver disease is associated with an increased incidence of atrial fibrillation in patients with type 2 diabetes.
      • Targher G.
      • Valbusa F.
      • Bonapace S.
      • et al.
      Association of nonalcoholic fatty liver disease with QTc interval in patients with type 2 diabetes.
      Patients with NAFLD are at an increased risk of CVD. One study from National Health and Nutrition Examination Survey-III database demonstrated that patients with advanced hepatic fibrosis from NAFLD had a 70% increased risk of all-cause mortality, and even after adjusting for multiple cardiac risk factors, the mortality was found to be almost entirely due to CVD.
      • Kim D.
      • Kim W.R.
      • Kim H.J.
      • Therneau T.M.
      Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States.
      Another study found the 10-year risk of acute coronary events in patients with NAFLD to be 4-fold higher compared with controls.
      • Guleria A.
      • Duseja A.
      • Kalra N.
      • et al.
      Patients with non-alcoholic fatty liver disease (NAFLD) have an increased risk of atherosclerosis and cardiovascular disease.
      In other studies, patients with biopsy/imaging–proven NAFLD with or without T2DM are associated with increased risk of CVD.
      • Rafiq N.
      • Bai C.H.
      • Fang Y.
      • et al.
      Long-term follow-up of patients with nonalcoholic fatty liver.
      • Targher G.
      • Bertolini L.
      • Rodella S.
      • et al.
      Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients.
      Degree of fibrosis in NAFLD patients predicts the long-term outcomes with risk for extra-hepatic morbidity and mortality. The risk for cardiac events and mortality also remains among transplant patients while they are waiting for receiving the organ and during the posttransplant period.
      • VanWagner L.B.
      • Bhave M.
      • Te H.S.
      • Feinglass J.
      • Alvarez L.
      • Rinella M.E.
      Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events.
      • Piazza N.A.
      • Singal A.K.
      Frequency of cardiovascular events and effect on survival in liver transplant recipients for cirrhosis due to alcoholic or nonalcoholic steatohepatitis.
      Given the higher incidence and mortality due to NAFLD in CVD patients, screening should be considered in intermediate, and higher risk patients should be referred to cardiologist for evaluation. However, the data are still limited in terms of appropriate screening modalities. Patients with NASH cirrhosis undergoing liver transplantation evaluation should be screened for significant coronary artery disease (CAD). Screening modalities include stress echocardiography and CT coronary angiography. Conventional angiography is reserved for patients with combination of risk factors for CAD.

      NAFLD and Type 2 Diabetes Mellitus

      The relation between NAFLD and T2DM is complex and bidirectional. Prevalence of NAFLD among patients with T2DM is increased with varying rates of 10–75% among different series. The risk varies depending upon degree and control of diabetes and presence and severity of other components of MetS. On the other hand, among NAFLD subjects, the prevalence of T2DM varies between 18 and 33% depending on the severity of NAFLD. For example, the prevalence of T2DM was 7% among patients without NAFLD, 9.8% with mild NAFLD, and 17.8% in subjects with moderate to severe NAFLD.
      • Ekstedt M.
      • Franzen L.E.
      • Mathiesen U.L.
      • et al.
      Long-term follow-up of patients with NAFLD and elevated liver enzymes.
      • Loomba R.
      • Abraham M.
      • Unalp A.
      • et al.
      Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.
      T2DM is also associated with progression of NAFLD to steatohepatitis, cirrhosis, and hepatocellular carcinoma.
      • Anstee Q.M.
      • Targher G.
      • Day C.P.
      Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis.
      NAFLD is also associated with microvascular complications of T2DM including retinopathy and CKD.
      • Targher G.
      • Bertolini L.
      • Rodella S.
      • et al.
      Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients.
      Further, the incidence for new-onset T2DM is about 2–3 folds increased among NAFLD patients as assessed in two different large meta-analyses.
      • Musso G.
      • Gambino R.
      • Cassader M.
      • Pagano G.
      Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity.
      • Fraser A.
      • Harris R.
      • Sattar N.
      • Ebrahim S.
      • Davey Smith G.
      • Lawlor D.A.
      Alanine aminotransferase, gamma-glutamyltransferase, and incident diabetes: the British Women's Heart and Health Study and meta-analysis.
      The risk is increased irrespective of the modality for NAFLD diagnosis, biochemical, imaging, or histological. Further, alanine aminotransferase and gamma glutamyl trans peptidase levels were independent predictors for incident T2DM.
      • Musso G.
      • Gambino R.
      • Cassader M.
      • Pagano G.
      Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity.
      • Fraser A.
      • Harris R.
      • Sattar N.
      • Ebrahim S.
      • Davey Smith G.
      • Lawlor D.A.
      Alanine aminotransferase, gamma-glutamyltransferase, and incident diabetes: the British Women's Heart and Health Study and meta-analysis.
      One prospective study assessed the incidence of T2DM in biopsy proven NAFLD and found that among 129 patients, a total of 58% developed T2DM and 20% developed impaired glucose tolerance during a follow-up period of 13.7 years. Patients with NASH had a 3-fold higher risk of developing T2DM compared with simple fibrosis.
      • Ekstedt M.
      • Franzen L.E.
      • Mathiesen U.L.
      • et al.
      Long-term follow-up of patients with NAFLD and elevated liver enzymes.
      Based on these data, it is recommended to screen NAFLD patients (a) without T2DM for annual assessment of hemoglobin A1C and (b) with established T2DM for annual retinal examination and microalbuminuria with urinary albumin to creatinine ratio.

      NAFLD And Chronic Kidney Disease

      The relationship between NAFLD and CKD is still unclear. Studies suggest that the presence of NAFLD may accelerate the development and progression of CKD independent of the traditional risk factors.
      • Musso G.
      • Gambino R.
      • Tabibian J.H.
      • et al.
      Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.
      • Musso G.
      • Cassader M.
      • Cohney S.
      • Pinach S.
      • Saba F.
      • Gambino R.
      Emerging liver-kidney interactions in nonalcoholic fatty liver disease.
      Impaired antioxidant mechanism, upregulation of the renin–angiotensin system, and dietary factors potentially mediate the development of CKD among NAFLD patients.
      • Musso G.
      • Gambino R.
      • Cassader M.
      Emerging molecular targets for the treatment of nonalcoholic fatty liver disease.
      Additionally, CKD is associated with alterations in gut microbiota and increased gut permeability which may lead to progression of NAFLD.
      • Musso G.
      • Gambino R.
      • Cassader M.
      Emerging molecular targets for the treatment of nonalcoholic fatty liver disease.
      A recent meta-analysis evaluated the risk of CKD with NAFLD and found that NAFLD was associated with an increased prevalence (odds ratio [OR] 2.12, 95% confidence interval [CI] 1.69–2.66) and incidence (hazard ratio [HR] 1.79, 95% CI 1.65–1.95) of CKD. NASH was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Further, the NAFLD spectrum and severity was associated with higher and worst CKD stage in this meta-analysis. These findings were independent of T2DM and other traditional risk factors.
      • Musso G.
      • Gambino R.
      • Tabibian J.H.
      • et al.
      Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.
      However, another study did not find such an association.
      • Choudhary N.S.
      • Saraf N.
      • Kumar N.
      • et al.
      Nonalcoholic fatty liver is not associated with incident chronic kidney disease: a large histology-based comparison with healthy individuals.
      Nevertheless, because of the higher risk of CKD in NAFLD subjects, it is recommended to protect kidneys with cautious and judicious use of nephrotoxic drugs and regularly screening their renal function. The increased risk of CKD in NAFLD patients probably accounts for NASH cirrhosis as the leading and most rapidly growing indication for simultaneous liver kidney transplantation.
      • Singal A.K.
      • Hasanin M.
      • Kaif M.
      • Wiesner R.
      • Kuo Y.F.
      Nonalcoholic steatohepatitis is the most rapidly growing indication for simultaneous liver kidney transplantation in the United States.
      Recipients of liver transplant alone for NASH cirrhosis also remain at risk for poorer renal function with risk of CKD during the posttransplant follow-up.
      • Molnar M.Z.
      • Joglekar K.
      • Jiang Y.
      • et al.
      Association of pre-transplant renal function with liver graft and patient survival after liver transplantation in patients with nonalcoholic steatohepatitis.
      • Singal A.K.
      • Hasanin M.
      • Kaif M.
      • Wiesner R.W.
      • Kuo Y.F.
      MELD stratified outcomes among recipients with diabetes or hypertension: simultaneous liver kidney versus liver alone.
      Although studies have suggested that NAFLD may accelerate progression of CKD, screening for NAFLD in CKD patients is not routinely performed, and there is no specific guideline for screening NAFLD in CKD patients. Further studies are required to determine the approach and the clinical management of NAFLD in CKD patients.

      NAFLD and Obstructive Sleep Apnea

      Obesity among patients with MetS and NAFLD leads to upper airway collapse with airway edema leading to chronic intermittent hypoxia, which further leads to worsening of insulin resistance and risk for NAFLD.
      • Schelbert K.B.
      Comorbidities of obesity.
      • Agrawal S.
      • Duseja A.
      • Aggarwal A.
      • et al.
      Obstructive sleep apnea is an important predictor of hepatic fibrosis in patients with nonalcoholic fatty liver disease in a tertiary care center.
      Several studies have suggested that OSA leads to liver injury and further worsening of NAFLD.
      • Tanne F.
      • Gagnadoux F.
      • Chazouilleres O.
      • et al.
      Chronic liver injury during obstructive sleep apnea.
      • Jouet P.
      • Sabate J.M.
      • Maillard D.
      • et al.
      Relationship between obstructive sleep apnea and liver abnormalities in morbidly obese patients: a prospective study.
      The association of OSA and NAFLD is observed among both children and adults.
      • Jouet P.
      • Sabate J.M.
      • Maillard D.
      • et al.
      Relationship between obstructive sleep apnea and liver abnormalities in morbidly obese patients: a prospective study.
      • Aron-Wisnewsky J.
      • Minville C.
      • Tordjman J.
      • et al.
      Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese.
      A meta-analysis showed that the patients with OSA were at increased risk of NAFLD, NASH, and advanced fibrosis irrespective of the age, sex, and body mass index.
      • Musso G.
      • Cassader M.
      • Olivetti C.
      • Rosina F.
      • Carbone G.
      • Gambino R.
      Association of obstructive sleep apnoea with the presence and severity of non-alcoholic fatty liver disease. A systematic review and meta-analysis.
      In another meta-analysis, OSA increased advanced spectrum from NAFLD with 2–3 folds increased risk of NAFLD and of advanced disease. This risk was present after controlling for traditional risk factors including patient's age, gender, degree of obesity, and body mass index.
      • Musso G.
      • Cassader M.
      • Olivetti C.
      • Rosina F.
      • Carbone G.
      • Gambino R.
      Association of obstructive sleep apnoea with the presence and severity of non-alcoholic fatty liver disease. A systematic review and meta-analysis.
      Based on these data, it is recommended to screen obese patients with NAFLD for possible OSA and patients with established OSA for underlying NAFLD. Another pulmonary issue in NAFLD patients is hyper responsive airways with asthma because of increased levels of leptin and generalized proinflammatory state in NAFLD.
      • Molnar M.Z.
      • Joglekar K.
      • Jiang Y.
      • et al.
      Association of pre-transplant renal function with liver graft and patient survival after liver transplantation in patients with nonalcoholic steatohepatitis.

      NAFLD and Osteoporosis

      Chronic liver disease patients are at higher risk of developing metabolic bone disease; however, the relationship between osteoporosis and NAFLD is still poorly understood. A study among both children and adults suggested that patients with NAFLD had low bone mineral density compared with patients without NAFLD.
      • Targher G.
      • Lonardo A.
      • Rossini M.
      Nonalcoholic fatty liver disease and decreased bone mineral density: is there a link?.
      A large population-based study in China studied the prevalence of osteoporotic fractures and found that Chinese men with NAFLD had higher incidence compared with men without NAFLD (3.6% vs. 1.5%, P < 0.005). The increased risk was not seen among Chinese women. On multivariate regression analysis, the risk remained elevated among Chinese men independent of multiple potential confounders.
      • Li M.
      • Xu Y.
      • Xu M.
      • et al.
      Association between nonalcoholic fatty liver disease (NAFLD) and osteoporotic fracture in middle-aged and elderly Chinese.
      It should be noted that this assessment was based on self-report by the patients and not based on bone density evaluation. Screening guidelines for osteoporosis among NAFLD patients are as for any other patient. Clearly, further studies are warranted to explore and validate this association.

      NAFLD and Colorectal Cancer

      Insulin resistance with hyperinsulinemia and proinflammatory state with oxidative stress mediate cellular proliferation and risk for malignancy. The risk is particularly observed for colorectal cancer, the third most common cancer worldwide with approximately 1.2 million cases diagnosed annually.
      • Ferlay J.
      • Shin H.R.
      • Bray F.
      • Forman D.
      • Mathers C.
      • Parkin D.M.
      Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008.
      The incidence of colorectal cancer and adenoma is increased among patients with MetS; however, studies evaluating increased risk for colorectal cancer in patients with NAFLD have shown conflicting results.
      • Jinjuvadia R.
      • Lohia P.
      • Jinjuvadia C.
      • Montoya S.
      • Liangpunsakul S.
      The association between metabolic syndrome and colorectal neoplasm systemic review and meta-analysis.
      In a meta-analysis of 5 studies on over 6000 patients, NAFLD was associated with about 2-folds risk of colorectal adenoma, the risk was highest among Asian population and among patients with NASH.
      • Ding W.J.
      • Fan J.G.
      • Qin J.J.
      Association between nonalcoholic fatty liver disease and colorectal adenoma: a systematic review and meta-analysis.
      Despite having an increased risk, there was no association established between NAFLD and NASH with colorectal cancer. However, this analysis was limited with retrospective studies and short follow-up period of about 10 years. Hence, further large prospective studies are needed to establish the association between NAFLD and colorectal cancer. NAFLD patients are screened for colorectal adenoma or cancer as per current guidelines for any other patient. Other sites for increased cancer risk among NAFLD patients are breast, endometrium, prostate, kidneys, and esophagus. Specifically, in the esophagus, the risk is increased for gastroesophageal reflux with potential for Barrett's esophagus and subsequent adenocarcinoma of the esophagus.
      • Molnar M.Z.
      • Joglekar K.
      • Jiang Y.
      • et al.
      Association of pre-transplant renal function with liver graft and patient survival after liver transplantation in patients with nonalcoholic steatohepatitis.

      NAFLD and Hypothyroidism

      Thyroid hormone is an important regulator of metabolic processes in the body. Additionally, hypothyroidism is associated with dyslipidemia and obesity, which in turn promote the progression of NAFLD.
      • Chung G.E.
      • Kim D.
      • Kim W.
      • et al.
      Non-alcoholic fatty liver disease across the spectrum of hypothyroidism.
      A systematic review of 11 studies with 12,924 participants found that the prevalence of hypothyroidism in NAFLD is 15.2–36.3%, and the prevalence was higher in NASH patients compared with those without NASH.
      • Eshraghian A.
      • Hamidian Jahromi A.
      Non-alcoholic fatty liver disease and thyroid dysfunction: a systematic review.
      On the other hand, prevalence of NAFLD was higher among patients with primary hypothyroidism including patients with subclinical disorder with upper normal thyroid stimulating hormone (TSH) levels. It is recommended to screen NAFLD patients annually for TSH levels.
      • Chung G.E.
      • Kim D.
      • Kim W.
      • et al.
      Non-alcoholic fatty liver disease across the spectrum of hypothyroidism.
      Further studies are needed to assess if there is any causal relationship between NAFLD and hypothyroidism and if thyroid replacement therapy has any impact on course of progression of liver disease.

      NAFLD and Polycystic Ovarian Syndrome

      PCOS is a syndrome that affects women of reproductive age and manifests as hyper androgenism, cystic appearing ovaries, and oligomenorrhea. Like NAFLD, patients with PCOS have insulin resistance and obesity and are at higher risk of CVD. Additionally, up to 50% of patients with PCOS have hepatic steatosis.
      • Kelley C.E.
      • Brown A.J.
      • Diehl A.M.
      • Setji T.L.
      Review of nonalcoholic fatty liver disease in women with polycystic ovary syndrome.
      One meta-analysis including 7 studies found that patients with PCOS had almost 4-fold increased prevalence of co-existing NAFLD.
      • Ramezani-Binabaj M.
      • Motalebi M.
      • Karimi-Sari H.
      • Rezaee-Zavareh M.S.
      • Alavian S.M.
      Are women with polycystic ovarian syndrome at a high risk of non-alcoholic fatty liver disease; a meta-analysis.
      PCOS women with NAFLD have a higher prevalence of MetS and more insulin resistance compared with patients without NAFLD, with no significant difference between the serum levels of androgenic hormones.
      • Ramezani-Binabaj M.
      • Motalebi M.
      • Karimi-Sari H.
      • Rezaee-Zavareh M.S.
      • Alavian S.M.
      Are women with polycystic ovarian syndrome at a high risk of non-alcoholic fatty liver disease; a meta-analysis.
      • Targher G.
      • Rossini M.
      • Lonardo A.
      Evidence that non-alcoholic fatty liver disease and polycystic ovary syndrome are associated by necessity rather than chance: a novel hepato-ovarian axis?.
      Given the current evidence, careful screening and evaluation for NAFLD among PCOS patients is important given these patients are generally young and have high risk of developing long-term liver-related complications.

      NAFLD and Skin Manifestations

      Patients with autoimmune chronic inflammatory skin disorder of psoriasis have higher prevalence of MetS and NAFLD. This association is directly proportional to severity of psoriasis.
      • Mallbris L.
      • Ritchlin C.T.
      • Stahle M.
      Metabolic disorders in patients with psoriasis and psoriatic arthritis.
      • van der Voort E.A.M.
      • Koehler E.M.
      • Dowlatshahi E.A.
      • et al.
      Psoriasis is independently associated with nonalcoholic fatty liver disease in patients 55 years old or older: results from a population-based study.
      Whether incident psoriasis is higher among NAFLD patients remains unclear. It remains unclear whether this association is truly with psoriasis or because of drugs used to treat psoriasis, especially methotrexate. Other dermatologic issues in these patients due to underlying insulin resistance are acanthosis nigricans, keratosis, and hirsutism.
      • Molnar M.Z.
      • Joglekar K.
      • Jiang Y.
      • et al.
      Association of pre-transplant renal function with liver graft and patient survival after liver transplantation in patients with nonalcoholic steatohepatitis.
      Further, obesity in these patients results in reduced skin barrier function with dysfunctional sweat and sebaceous gland activity. Further, obesity has mechanical impact leading to higher prevalence of varicose veins with resultant effects of lymphedema, varicose ulcers, cellulitis, and fasciitis
      • Molnar M.Z.
      • Joglekar K.
      • Jiang Y.
      • et al.
      Association of pre-transplant renal function with liver graft and patient survival after liver transplantation in patients with nonalcoholic steatohepatitis.

      NAFLD and Hematological Disorders

      NAFLD is associated with increased ferritin levels, iron overload, and hepatic iron deposition. The degree and severity of iron overload in NAFLD patients is associated with degree of liver fibrosis and with risk for hepatocellular carcinoma
      • Kowdley K.V.
      • Belt P.
      • Wilson L.A.
      • et al.
      Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease.
      • Sorrentino P.
      • D'Angelo S.
      • Ferbo U.
      • Micheli P.
      • Bracigliano A.
      • Vecchione R.
      Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis.
      Although the body of evidence suggesting the association of increased ferritin level and liver injury in NAFLD is reasonably strong, few studies have found no clear association.
      • Valenti L.
      • Fracanzani A.L.
      • Bugianesi E.
      • et al.
      HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease.
      • Duseja A.
      • Das R.
      • Nanda M.
      • Das A.
      • Garewal G.
      • Chawla Y.
      Nonalcoholic steatohepatitis in Asian Indians is neither associated with iron overload nor with HFE gene mutations.
      In one of these studies, serum ferritin concentration did not predict fibrosis stage >1 in NAFLD patients, although the proportion of patients with fibrosis stage >1 in this cohort was relatively small.
      • Valenti L.
      • Fracanzani A.L.
      • Bugianesi E.
      • et al.
      HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease.
      Further, therapeutic phlebotomy in one study among NAFLD patients reduced the iron indices significantly, but without any effect on insulin resistance or hepatic histology.
      • Adams L.A.
      • Crawford D.H.
      • Stuart K.
      • et al.
      The impact of phlebotomy in nonalcoholic fatty liver disease: a prospective, randomized, controlled trial.
      Additionally, these patients may develop anemia in response to phlebotomy in contrast to experience of phlebotomy among primary hemochromatosis patients. Proinflammatory activity with elevated levels of plasminogen activator inhibitor-I among NAFLD patients results in low level activation of the coagulation cascade, resulting in increased risk of thrombophilia and vascular thrombosis.
      • Byrne C.D.
      • Targher G.
      NAFLD: a multisystem disease.
      Among patients with cirrhosis, NASH etiology is the leading cause for portal venous thrombosis. Further, transplant recipients for NASH cirrhosis compared with those without pretransplant portal venous thrombosis have higher risk for poorer posttransplant graft and patient survival.
      • Agbim U.
      • Jiang Y.
      • Kedia S.K.
      • et al.
      Impact of nonmalignant portal vein thrombosis in transplant recipients with nonalcoholic steatohepatitis.
      During the past decade, it has become clear there is an increased risk of CVD, T2DM, and CKD among NAFLD patients (Table 1), with risk for mortality from causes other than liver related, especially from malignancy and cardiovascular causes. Physicians and patients with NAFLD (particularly with fibrosis/NASH) should be aware of these increased risks while managing patients with NAFLD. When appropriate, patients may benefit from appropriate pharmaceutical therapies including lipid lowering agent and insulin sensitizers which will help to limit progression of NAFLD and decrease risk for extrahepatic manifestations. Further studies with longer follow-up are needed that collect detailed cardiometabolic risk profiles of these patients at baseline and over course of follow-up period for evaluating the impact of NAFLD as a systemic disease. Additionally, clinical trials examining the effect of treatment of NAFLD on risks and outcomes of its extra-hepatic manifestations are warranted.
      Table 1Principal Meta-analyses Examining Association Between Nonalcoholic Fatty Liver Disease and Various Comorbidities.
      ComorbiditiesStudyTypeOdds ratio (95% CI)
      Cardiovascular diseaseZhou et al., 2018Meta-analysis2.20 (1.67–2.90)
      Incident type 2 diabetesMarrison et al., 2019Meta-analysis2.17 (1.77, 2.65)
      Chronic kidney diseaseMantovani et al., 2018Meta-analysis1.37 (1.20–1.53)
      Obstructive sleep apneaMusso, 2013Meta-analysis2.37 (1.59–3.51)
      Colorectal cancerHuafeng, 2014Meta-analysis1.74 (1.53–1.97)
      HypothyroidismMantovani, 2018Meta-analysis1.42 (1.15–1.77)
      PsoriasisCandia, 2015Meta-analysis2.15 (1.57–2.94)
      CI: confidence interval.

      Author contributions

      Raseen Tariq wrote the paper, Page Axley edited the paper, and Ashwani Singal edited, revised, and contributed with conceptual development.

      Conflicts of interest

      The authors have none to declare.

      Funding

      This activity was supported by Faculty Development Grant to AKS from the American College of Gastroenterology and Internal Grant from the Avera Transplant Institute and Human Genetics Research Institute .

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